The devil is in the details

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2 The cobas KNOW THE RISK For cervical cancer prevention The devil is in the details Leading with the cobas as your primary screening method uncovers disease missed by cytology, and can protect women from unnecessary interventions. 1,2

3 In cervical cancer screening Protect women from cervical cancer and from overtreatment The goals of cervical cancer screening have remained elusive Identifying as many women as possible at risk of precancer Balancing high sensitivity and negative predictive value with high specificity to protect women from unnecessary interventions and lower the burden on the healthcare system Cytology has a changing role Cytology screening, including triage of abnormal cytology results, has been useful in significantly reducing the incidence and mortality rate of cervical cancer 3 Cytology has relatively low sensitivity, resulting in missed disease in women 1 Variable sample quality and subjective interpretation of cell morphology means Pap tests alone may not catch women at high risk or who have pre-cervical cancer 1 Cytology does not reliably detect cellular changes caused by adenocarcinoma 4 Normal cytology does not always mean cancer-free Up to one-third of cervical cancers occur in screened women with normal Pap cytology 5.6 New strategies are needed to deliver improved patient care while avoiding unnecessary treatment The discovery of HPV as the cause of cervical cancer revolutionized cervical cancer prevention strategies 2,3,7 Evidence supports moving to testing for primary screening of cervical cancer 2 - In primary screening, testing was proven more sensitive than cytology for detecting CIN2+ and CIN3+ 8 Pooled testing has high sensitivity but lacks specificity, accurately identifying women harboring disease, but resulting in false identification of healthy women, leading to unnecessary colposcopy 9 Evidence supports that there is an opportunity to identify those at highest risk, since 70% of cervical cancers are caused by HPV genotypes 16 and 18 3 The case for using the cobas for primary screening In the ATHENA study, the cobas found 92% of cases of CIN3 in the overall population compared to 53% found by cytology 1 cobas detected more CIN3 cases in overall population than liquid-based cytology 1 cobas 252 In the ATHENA study, 274 cases of CIN3 were found in a screening population of 47,208 women; the cobas found 252 (92%) of these cases. found 146 (53%) of these cases Emerging strategies 32 % 24 % Kaiser Permanente and 2 other healthcare plans 5 N = 833 Swedish healthcare system 6 N = 1230 The cobas offers an opportunity to strive for both goals of screening it provides pooled results on the known 12 high-risk genotypes and individual results on the highest-risk genotypes HPV 16 and 18, identifying women with the highest likelihood of harboring high-grade disease, while following a triage strategy that protects women from unnecessary intervention 1 Percentage of invasive cervical cancer that occurred in women with normal cytology 5,6 High-risk HPV genotypes Highest-risk HPV genotypes

4 Pooled testing provides only part of the answer Preventing more cancer over time than cytology 2,10 Pooled testing provides increased sensitivity for disease A systematic evidence review of randomized studies shows pooled test sensitivity was 86% 97% vs 46% 50% for cytology for a CIN3, and the range for CIN2 was 63% 98% for compared to 38% 65% for cytology 8 The clinical dilemma: The HPV-positive woman CONFIDENCE P HPV-negative QUESTION? HPV-positive Sensitivity for CIN2 (%) Bigras (N=13,842) Cardenas (N=1,850) Sensitivity of cytology vs for CIN2 Coste (N=3,080) Kulasingam (N=774) Mayrand (N=9,977) Petry (N=7,908) Average increase 36% test Cytology Absolute test performance of primary screening with HPV testing alone compared to cytology alone in developed countries in women aged 30 years or older 8 99% negative predictive value 1 Long-term protective benefit of DNA is well proven 1 High risk of false-positives due to lack of specificity 3 False-positives have an unnecessary adverse psychosocial impact on women 12 Pooled testing Pooled testing allows detection and treatment of precancers missed by cytology, thereby preventing more cancer than cytology alone 10 In a randomized controlled trial of 94,370 women, no cancers were found in the second round of screening among HPV-positive women referred to colposcopy in the first round, indicating that all precancers were identified in the initial round 10 A woman negative for HPV can be managed differently than a woman positive for high-risk genotypes 11 Following each -positive test result with colposcopy places large burden on the healthcare system Screening Round 1 (time 0) Round 1 Cancer Round 1 CIN The screening interval can be safely extended for HPV-negative women 11 Dilemma: Inability to discern who would benefit from immediate colposcopy without further triage 9 Screening Round 2 (+4 years) Round 2 Cancer Round 2 CIN3 0 HPV 0 cases of cancer detected Total Total Cancer Total CIN HPV Cytology Triage strategies are needed to determine who would benefit most from colposcopy now vs those who could be managed less aggressively. This would maximize the benefits of cervical cancer screening while decreasing the potential harm. 9 No. of cases HPV-based screening reduces the incidence of cervical cancer within 4 5 years, compared to cytology-based screens. 2,10

5 HPV 16 and HPV 18 bring clarity Adding greater specificity to pooled Focus on women at the highest risk HPV 16 and HPV 18 are responsible for approximately two-thirds of cervical cancer cases 3 Women HPV 16-positive and HPV 18-positive are at increased risk of CIN3, even if they have normal baseline and repeat cytologies 13 In a 10-year study of women with normal cytology, women HPV 16-positive or HPV 18-positive were more likely to have CIN3 over a 10-year period than women who were positive for other pooled HPV genotypes 14 For women who were HPV 16-positive at baseline, the incidence rose sharply during the first year of the study 14 For HPV 18-positive women, the incidence of CIN3 increased from around 2 years after baseline year cumulative incidence rate of CIN3 by status 14 HPV 16 and HPV 18 cause 70% of cervical cancers and are the two most prevalent oncogenic HPV genotypes in both squamous cell carcinoma and adenocarcinoma 4 Cumulative Incidence Rate, % (Confidence Interval) Follow-up Time (months) HPV % (11.5, 22.9) HPV % (3.6, 23.7) Other pooled 3.0% (1.9, 4.2) HPV 0.8% (0.6, 1.1) HPV 16 causes 55% 60% of cervical cancer 3 HPV 18 causes a significant proportion of adenocarcinomas, which are hard to detect by cytology 4 The pooled HPV genotypes were as follows: HPV 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. Adapted from Khan MJ, et al. J Natl Cancer Inst. 2005;97: HPV 16 and HPV 18 genotyping add specificity to further define risk 1 Adding HPV 16/18 genotyping to a pooled with cytology triage strategy maintains sensitivity and adds greater specificity, and therefore, greater positive predictive value vs the current standard of care. 1,15 HPV 16 and HPV 18 Conforms to US guidelines, which recognize the benefits of identifying HPV 16 or HPV 16/18. 3 The cobas KNOW THE RISK

6 The cobas 3 tests in 1 for confident risk stratification ATHENA: Powered to change the standard of testing 1 ATHENA is a multicenter, prospective trial of more than 47,000 women 21 years of age undergoing routine cervical cancer screening. The cobas is the only clinically validated, CE-marked and FDA-approved* test that simultaneously provides pooled results on known high-risk genotypes and individual results on the 2 highestrisk genotypes, HPV 16 and HPV 18, giving 3 results in just 1 test. Most HPV tests 14 pooled cobas pooled STUDY VISIT 1: STUDY VISIT 2: Cytology and HPV testing were performed on all women. All women with ASC-US cytology or -positive test results and a random subset of women 25 years of age who had normal cytology and were negative underwent colposcopy and biopsy. 14 pooled: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68 ATHENA The most comprehensively designed, evidence-based study ever conducted to evaluate HPV screening strategies 1,16 The ATHENA trial (N=47,208) is a landmark study and is the largest US registration study for cervical cancer screening, and the only study to assess the value of simultaneous HPV 16 and 18 genotyping in risk assessment of women 16 Supports effective triage at primary screening by providing high sensitivity with testing and high specificity by isolating the highest cervical cancer risk HPV genotypes to identify patients who need immediate intervention 1 The ATHENA trial evaluated the performance of the cobas in multiple clinical situations representing 3 scenarios for its intended use, including 16 : 1. As a triage test for ASC-US cytology in cytology-based screening (ASC-US triage) 2. As a screening test alongside cytology (co-testing) 3. As a stand-alone screening test (primary screening)* 3-YEAR LONGITUDINAL FOLLOW-UP: Women without a histological diagnosis of CIN2 had annual follow-up visits for the next 3 years, at which those with abnormal cytology undergo colposcopy and biopsy; those with a histologic diagnosis of CIN2 exited the study. Exit colposcopy was offered to all women. Women with a histological diagnosis of CIN2 met the endpoint and exited the study. Because the devil is in the details, order the evidence-based cobas *The cobas is not approved for primary screening in the US. Addressing THE Need for Advanced HPV Diagnostics The cobas KNOW THE RISK cobas

7 The cobas Integral to cervical cancer prevention The optimal primary screening strategy focuses medical attention on women with genotypes HPV 16 and HPV 18, and triages other high-risk genotypes. 2,9 The potential to set the new standard of care, providing significantly enhanced patient risk stratification 9,18 Primary screening strategies for the detection of CIN3 endpoint 9 Cytology with reflex HPV Current standard of care Had low sensitivity for detection of CIN3 9 Less efficient strategy, as it requires frequent screening (at least every 2 3 years) 9, HPV with genotyping and reflex cytology 72% CIN3 cases 7.2 colposcopies per CIN3 case HPV with genotyping and reflex cytology HPV with reflex cytology Almost 1.3 times more cases than the current standard of care 9 care, as only 7.2 colposcopies were necessary to detect a single case of CIN3 vs 7.7 9,17 Identified a similar amount of disease as strategy that used cytology as primary screen 9 care, as 6.1 colposcopies were needed to detect a single case of CIN3 vs the 7.7 required by cytology 9,17 % of CIN3 cases at baseline detected HPV screening alone 90% CIN3 cases 13.8 colposcopies per CIN3 case HPV with reflex cytology 52% CIN3 cases 6.1 colposcopies per CIN3 case Cytology with reflex HPV 56% CIN3 cases 7.7 colposcopies per CIN3 case # of colposcopies to detect a single case of CIN3 Most sensitive screening strategy finding significantly more disease than cytology alone 9 HPV screening alone Highest false-positive rate for CIN3 9 Inefficient strategy, as it required 13.8 colposcopies to find a single case of CIN3 9,17

8 % of CIN3 cases at baseline detected The cobas Integral to cervical cancer prevention The optimal primary screening strategy focuses medical attention on women with genotypes HPV 16 and HPV 18, and triages other high-risk genotypes. 2,9 The potential to set the new standard of care, providing significantly enhanced patient risk stratification 9,18 Cytology with reflex HPV Current standard of care Had low sensitivity for detection of CIN3 9 Less efficient strategy, as it requires frequent screening (at least every 2 3 years) 9,17 Primary screening strategies for the detection of CIN3 endpoint NILM ASC-US LSIL/HSIL HPV test Negative Positive HPV with genotyping and reflex cytology 72% CIN3 cases 7.2 colposcopies per CIN3 case HPV with genotyping and reflex cytology Almost 1.3 times more cases than the current standard of care 9 care, as only 7.2 colposcopies were necessary to detect a single case of CIN3 vs 7.7 9,17 cobas HPV- HPV 16/18+* 60 HPV screening alone 90% CIN3 cases 13.8 colposcopies per CIN3 case NILM ASC-US Follow-up in 12 months HPV with reflex cytology Identified a similar amount of disease as strategy that used cytology as primary screen 9 care, as 6.1 colposcopies were needed to detect a single case of CIN3 vs the 7.7 required by cytology 9,17 test HPV- NILM ASC-US HPV with reflex cytology 52% CIN3 cases 6.1 colposcopies per CIN3 case Cytology with reflex HPV 56% CIN3 cases 7.7 colposcopies per CIN3 case Follow-up in 12 months HPV screening alone Most sensitive screening strategy finding significantly more disease than cytology alone 9 Highest false-positive rate for CIN3 9 Inefficient strategy, as it required 13.8 colposcopies to find a single case of CIN3 9,17 test HPV- # of colposcopies to detect a single case of CIN3 *HPV 16-positive and/or 18-positive

9 The cobas Integral to cervical cancer prevention The optimal primary screening strategy focuses medical attention on women with genotypes HPV 16 and HPV 18, and triages other high-risk genotypes. 2,9 Almost 1.3 times more cases than the current standard of care Balances detected cases and intervention Screening tests % of CIN3 cases detected at baseline Colposcopies Colposcopies to detect 1 case of CIN3 Cytology with reflex HPV Current standard of care Had low sensitivity for detection of CIN3 9 Less efficient strategy, as it requires frequent NILM Negative ASC-US HPV test 35,546 56% screening (at least every 2 3 years) 9,17 Positive LSIL/HSIL HPV with genotyping and reflex cytology Almost 1.3 times more cases than the current standard of care 9 cobas ,423 72% 982 ASC-US to detect a single case of CIN3 vs 7.7 9, HPV 16/18+* care, as only 7.2 colposcopies were necessary HPV- HPV- NILM Follow-up in 12 months 7.2 HPV with reflex cytology Identified a similar amount of disease as strategy that used cytology as primary screen 9 care, as 6.1 colposcopies were needed to detect a single case of CIN3 vs the 7.7 HPV required by cytology 9, test NILM ASC-US Follow-up in 12 months 37,126 52% HPV screening alone Most sensitive screening strategy finding significantly more disease than cytology alone test ,254 90% 2, colposcopies to find a single case of CIN3 9, Highest false-positive rate for CIN3 9 Inefficient strategy, as it required 13.8 *HPV 16-positive and/or 18-positive Total CIN3 cases = 189 Total number of women screened = 34,254

10 The cobas An evidence-based approach to primary screening Help protect women from cervical cancer and from overtreatment The cobas, a pooled high-risk HPV test with simultaneous HPV 16 and HPV 18 genotyping, enables clinicians to use pooled HPV testing with or without individual HPV 16/18 genotyping to achieve significant advantages over the current standard of care 9 Allows early and efficient stratification of the few women who require aggressive intervention and those who are at very low risk 9 Permits confident extension of screening intervals 11 Identifies women who can return to routine screening 11 Conforms to US guidelines, which recognize the benefits of identifying HPV 16 or HPV 16/18 1 Use of simultaneous HPV 16/18 genotyping finds more cases of disease while reducing the burden on the healthcare system, compared to cytology-based screening 9 The devil is in the details, so implement primary screening with the cobas REFERENCES: 1. Castle PE, Stoler MH, Wright TC Jr, Sharma A, Wright TL, Behrens CM. Performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping for cervical cancer screening of women aged 25 years and older: a subanalysis of the ATHENA study [published online August 23, 2011]. Lancet Oncol. doi: /s (11) Rijkaart DC, Berkhof J, Rozendaal L, et al. Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomised controlled trial. Lancet Oncol. 2012;13: Saslow D, Solomon D, Lawson HW, et al. American Cancer Society, American Society for and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. Am J Clin Pathol. 2012;137(4): Herzog TJ, Monk BJ. Reducing the burden of glandular carcinomas of the uterine cervix. Am J Obstet Gynecol. 2007;197(6): Leyden WA, Manos MM, Geiger AM, et al. Cervical cancer in women with comprehensive health care access: attributable factors in the screening process. J Natl Cancer Inst. 2005;97(9): Andrae B, Kemetli L, Sparén P, et al. Screening-preventable cervical cancer risks: evidence from a nationwide audit in Sweden. J Natl Cancer Inst. 2008;100(9): Bosch FX, de Sanjosé S. Chapter 1: Human papillomavirus and cervical cancer burden and assessment of causality. J Natl Cancer Inst Monogr. 2003;31: Whitlock EP, Vesco KK, Eder M, Lin JS, Senger CA, Burda BU. Liquid-based cytology and human papillomavirus testing to screen for cervical cancer: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2011;155(10): Cox JT, Castle PE, Behrens CM, et al. Comparison of cervical cancer screening strategies incorporating different combinations of cytology, HPV testing and genotyping for HPV 16/18: results from the ATHENA HPV study. Am J Ob Gyn. 2012:In Press. 10. Ronco G, Giorgi-Rossi P, Carozzi F, et al. Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial. Lancet Oncol. 2010;11(3): Katki HA, Kinney WK, Fetterman B, et al. Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice. Lancet Oncol. 2011;12(7): Gray NM, Sharp L, Cotton SC, et al. Psychological effects of a low-grade abnormal cervical smear test result: anxiety and associated factors. British J Cancer. 2006:94(9): Berkhof J, Bulkmans NWJ, Bleeker MCG, et al. Human papillomavirus type specific 18-month risk of high-grade cervical intraepithelial neoplasia in women with a normal or borderline/mildly dyskaryotic smear. Cancer Epidemiol Biomarkers Prev. 2006;15(7): Khan MJ, Castle PE, Lorincz AT, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst. 2005;97(14): Stoler MH, Wright TC Jr, Sharma A, et al. High-risk human papillomavirus testing in women with ASC-US cytology: results from the ATHENA HPV study. Am J Clin Pathol. 2011;136: cobas [package insert, US]. Branchburg, NJ: Roche Molecular Systems, Inc.; Data on file, Roche Molecular Diagnostics, Inc. 18. Wright TC Jr, Stoler MH, Behrens CM, Apple R, Derrion T, Wright TL. The ATHENA human papillomavirus study: design, methods, and baseline results. Am J Obstet Gynecol. 2012;206(1):46.e1-46.e11. The cobas KNOW THE RISK For more information, go to COBAS is a trademark of Roche Roche Molecular Systems, Inc. Roche Molecular Diagnostics, Inc., 4300 Hacienda Drive, Pleasanton, CA USA